Body of uterus and endometrium

The uterus has two major components: the myometrium and the endometrium. The myometrium is composed of tightly interwoven bundles of smooth muscle that form the wall of the uterus. The internal cavity of the uterus is lined by the endometrium composed of glands embedded in a cellular stroma. The uterus is subject to a variety of disorders, the most common of which result from endocrine imbalances, complications of pregnancy, and neoplastic proliferation. Together with the lesions that affect the cervix (causing abnormal Pap smears), the lesions of the corpus of the uterus and the endometrium (causing abnormal vaginal bleeding) account for most patient visits to gynecologic practices.

Endometrial Histology in the Menstrual Cycle

The endometrium is a dynamic tissue that undergoes physiologic and characteristic morphologic changes during the menstrual cycle as a result of the effect of sex steroid hormones coordinately produced in the ovary. The ovary, in turn, is influenced by hormones produced by the pituitary. Together the hypothalamic, pituitary, and ovarian factors and their interactions regulate maturation of ovarian follicles, ovulation, and menstruation.

"Dating" the endometrium by its histologic appearance is often used clinically to assess hormonal status, document ovulation, and determine causes of endometrial bleeding and infertility (Fig. 22-22). The cycle begins with the shedding of the upper half to two thirds of the endometrium, referred to as the functionalis (the hormonally responsive upper zone), during menses. Under the influence of estrogen, produced by the granulosa cells of the developing follicle in the ovary, the remaining third (basalis) of the endometrium undergoes extremely rapid growth of both glands and stroma (proliferative phase). During the proliferative phase the glands are straight, tubular structures lined by regular, tall, pseudostratified columnar cells. Mitotic figures are numerous, and there is no evidence of mucus secretion or vacuolation. The endometrial stroma is composed of thickly compacted spindle cells that have scant cytoplasm but abundant mitotic activity (Fig. 22-22A).

At the time of ovulation the endometrium slows in its growth, and it ceases mitotic activity within days after ovulation, at which time the corpus luteum is producing progesterone in addition to estrogen. The postovulatory endometrium is initially marked by secretory vacuoles beneath the nuclei in the glandular epithelium (Fig. 22-22B). This secretory activity is most prominent during the third week of the menstrual cycle, when the basal vacuoles progressively push past the nuclei. By the fourth week, the secretions are discharged into the gland lumens. When secretion is maximal, between 18 and 24 days, the glands are dilated. By the fourth week the glands are tortuous, producing a serrated appearance when they are cut in their long axis. This serrated or "saw-toothed" appearance is accentuated by secretory exhaustion and shrinking of the glands.

The stromal changes in late secretory phase, due predominantly to progesterone, are important for dating the endometrium and consist of the development of prominent spiral arterioles by days 21 to 22. A considerable increase in ground substance and edema between the stromal cells occurs and is followed in days 23 to 24 by stromal cell hypertrophy with accumulation of cytoplasmic eosinophilia (predecidual change) and resurgence of stromal mitoses (Fig. 22-22C). Predecidual changes spread throughout the functionalis during days 24 to 28 and are accompanied by scattered neutrophils and occasional lymphocytes, which in this context do not imply inflammation. With the dissolution of the corpus luteum and the subsequent lack of progesterone, the disintegration of the functionalis begins wi th the escape of blood into the stroma, marking the beginning of menstrual shedding (Fig. 22-22D).

Although the molecular mechanism(s) by which estrogen and progesterone cause these profound changes in the endometrium are not well understood, it is known that these hormones induce local production of molecules that act in an autocrine and paracrine fashion.31 Much of the hormonal action occurs through their cognate nuclear receptors (estrogen receptor α, progesterone receptor A, and progesterone receptor B). However, they may also act through alternate receptors or perhaps even by receptor-independent pathways.32 In addition, there is considerable cross-talk between the glands and stroma. For example, much of the effect of estrogen on glandular proliferation occurs via stromal cells, which in response to estrogen produce growth factors (e.g., insulin-like growth factor 1 and epidermal growth factor) that bind receptors expressed on the epithelial cells. In the secretory phase, progesterone initially inhibits proliferation in both the glands and the stroma. It also promotes differentiation of the glands and causes profound alterations of the stroma. Interestingly, progesterone secretion leads to a decrease in estrogen receptor expression in both the glands and stroma, making the endometrium relatively unresponsive to estrogen still being produced by the ovary. To further elucidate the mechanisms responsible for the hormonal effects, global gene expression studies are being used.33 It is thought that such information will aid in the treatment of women with disorders of the endometrium that range from infertility to cancer, as discussed below.

Functional Endometrial Disorders (Dysfunctional Uterine Bleeding)

During active reproductive life, the endometrium is in a dynamic state of proliferation, differentiation, and shedding, in preparation for implantation of an embryo. As discussed above, this cycle is exquisitely controlled by the rise and fall of pituitary and ovarian hormones, which is executed by proper timing of hormone release in both absolute and relative amounts. Abnormalities in this system result in abnormal uterine bleeding.

Although abnormal uterine bleeding can be caused by well-defined organic pathologic conditions, such as chronic endometritis, endometrial polyp (see Fig. 22-23C), submucosal leiomyomas (see Fig. 22-23D), or endometrial neoplasms, the largest single group encompasses functional disturbances, referred to as dysfunctional uterine bleeding (DUB; Table 22-3). DUB is a clinical term for uterine bleeding not caused by any underlying organic (structural) abnormality. The most common causes of DUB are discussed.